title: Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes.
abstract: OBJECTIVE
  Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is caused by FOXP3 mutations. We aimed to determine the prevalence, genetics, and clinical phenotype of FOXP3 mutations in a large cohort with permanent neonatal diabetes (PNDM).
  
  
  METHODS
  The 11 coding exons and the polyadenylation region of FOXP3 were sequenced in 26 male subjects with diabetes diagnosed before 6 months of age in whom common genetic causes of PNDM had been excluded. Ten subjects had at least one additional immune-related disorder, and the remaining 16 had isolated diabetes.
  
  
  RESULTS
  We identified four hemizygous FOXP3 mutations in 6 of 10 patients with associated immune-related disorders and in 0 of 16 patients with isolated diabetes (P = 0.002). Three patients with two novel mutations (R337Q and P339A) and the previously reported L76QfsX53 developed classic IPEX syndrome and died within the first 13 months. The novel mutation V408M was found in three patients from two unrelated families and had a mild phenotype with hypothyroidism and autoimmune enteropathy (n = 2) or nephrotic syndrome (n = 1) and survival to 12-15 years.
  
  
  CONCLUSIONS
  FOXP3 mutations result in approximately 4% of cases of male patients with permanent diabetes diagnosed before 6 months. Patients not only have classic IPEX syndrome but, unexpectedly, may have a more benign phenotype. FOXP3 sequencing should be performed in any male patient with the diagnosis of diabetes in the first 6 months who develops other possible autoimmune-associated conditions, even in the absence of full IPEX syndrome.
authors.affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK.
authors.forename: Oscar
authors.initials: O
authors.lastname: Rubio-Cabezas
authors.forename: Jayne A L
authors.initials: JA
authors.lastname: Minton
authors.forename: Richard
authors.initials: R
authors.lastname: Caswell
authors.forename: Julian P
authors.initials: JP
authors.lastname: Shield
authors.forename: Dorothee
authors.initials: D
authors.lastname: Deiss
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Sumnik
authors.forename: Amely
authors.initials: A
authors.lastname: Cayssials
authors.forename: Mathias
authors.initials: M
authors.lastname: Herr
authors.forename: Anja
authors.initials: A
authors.lastname: Loew
authors.forename: Vaughan
authors.initials: V
authors.lastname: Lewis
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
mesh_terms: D019943:Amino Acid Substitution; D001327:Autoimmune Diseases / Q000235:genetics; D002874:Chromosome Mapping; D041321:Chromosomes, Human, X; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors